Approximately 20 million people in the USA have been diagnosed with type 1 or 2 diabetes mellitus (DM). Type 2 DM accounts for 95% cases. The World Health Organization has estimated that more than 30 million people in the USA will be diagnosed with type 2 DM by 2030. DM patients often develop gastrointestinal (GI) complications, including gastroparesis, constipation and fecal incontinence. DM gastroparesis is defined as delayed gastric emptying in the absence of a mechanical obstruction and can be associated with symptoms such as gastro-esophageal reflux, nausea, vomiting bloating and abdominal pain. Gastroparesis makes gastric empting unpredictable, so blood glucose levels may be difficult to control. Diabetic gastropathy has a negative impact on quality of life. Previou studies, primarily utilizing animal models of type 2 DM have suggested that the GI symptoms result from enteric neuropathy, however recent studies have suggested defects in smooth muscle cells and changes in networks of interstitial cells of Cajal (ICC) and PDGFRa+ cells (SIP cells). Anatomical evaluations of human muscles from DM patients, including those of the NIDDK Gastroparesis Clinical Research Consortium (GpCRC), support the hypothesis that SIP cells are disrupted or reduced in type 2 DM. Clinical studies have been descriptive, however, and investigations into the impact of ICC loss and other mechanisms of DM gastropathy have not been performed in adequate depth. This project will use a multifaceted approach to test whether changes in gastric motor activity correlate with changes in SIP cell networks and function, changes in cell-specific expression of key genes of the pacemakersome and neuroeffectorsomes (remodeling), cellular defects in pacemaker and neuroeffector responses, and/or alterations in cyclooxygenase pathways that affect gastric muscle electrical and mechanical activities. Preliminary data provide novel insights into the basic mechanisms of DM gastropathy, and completion of the specific aims will provide new therapeutic rationales for normalization of DM motor dysfunction.